The Transcription Factor Nrf2 Protects Angiogenic Capacity of Endothelial Colony-Forming Cells in High-Oxygen Radical Stress Conditions

Gremmels, Hendrik; Jong, Olivier G. de; Hazenbrink, Diënty H. M.; Fledderus, Joost O.; Verhaar, Marianne C.

doi:10.1155/2017/4680612

Cited by 25 publications

(29 citation statements)

References 54 publications

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“…Increasing Nrf2 activity and its downstream target genes protects against EPC damage in DM, and the protective role of SDF-1 is reduced by silencing Nrf2 ( 22 ). Nrf2 serves an important role in the angiogenesis of EPCs, especially when cells are under oxidative stress ( 47 ). Previous reports have demonstrated that Nrf2 is downregulated in the nuclei of EPCs under high glucose treatment, including in DM ( 48 , 49 ).…”

Section: Discussionmentioning

confidence: 99%

Nrf2 protects against diabetic dysfunction of endothelial progenitor cells via regulating cell senescence

Wang

Liu

et al. 2018

Int J Mol Med

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Diabetes is associated with an increased risk of cardio-vascular disease. A decrease in the number and functionality of endothelial progenitor cells (EPCs) leads to reduced endothelial repair and the development of cardiovascular disease. The aim of the present study was to explore the effect and underlying mechanisms of nuclear factor erythroid 2-related factor 2 (Nrf2) on EPC dysfunction caused by diabetic mellitus. The biological functions of EPCs in streptozotocin-induced diabetic mice were evaluated, including migration, proliferation, angiogenesis and the secretion of vascular endothelial growth factor (VEGF), stromal-derived growth factor (SDF) and nitric oxide (NO). Oxidative stress levels in diabetic EPCs were also assessed by detecting intracellular reactive oxygen species (ROS), superoxide dismutase (SOD) and malondialdehyde (MDA). EPC senescence was evaluated by measuring p16 and b-gal expression and observing the senescence-associated secretory phenotype. In addition, the function of EPCs and level of oxidative stress were assessed following Nrf2 silencing or activation. Nrf2 silencing resulted in a decrease of EPC biological functions, accelerated cell senescence and increased oxidative stress, as indicated by ROS and MDA upregulation accompanied with decreased SOD activity. Furthermore, Nrf2 silencing inhibited migration, proliferation and secretion in EPCs, while it increased oxidative stress and cell senescence. Nrf2 activation protected diabetic EPCs against the effects of oxidative stress and cell senescence, ameliorating the biological dysfunction of EPCs derived from mice with diabetes. In conclusion, Nrf2 overexpression protected against oxidative stress-induced functional damage in EPCs derived from diabetic mice by regulating cell senescence.

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Section: Discussionmentioning

confidence: 99%

Nrf2 protects against diabetic dysfunction of endothelial progenitor cells via regulating cell senescence

Wang

Liu

et al. 2018

Int J Mol Med

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“…The capillary‐like tube formation and migration of human pulmonary microvascular ECs were largely suppressed by Nrf2 knockdown after oxygen–glucose deprivation and reoxygenation; in addition, nonphagocytic cell oxidase 4 and hypoxia‐inducible factor (HIF)‐1α expressions were also decreased due to lack of Nrf2 (Chai et al, 2018). Preincubation of endothelial colony‐forming cells (ECFCs) with sulforaphane (SFN) reduced the intracellular ROS and preserved the wound closure and tube formation abilities under oxidative stress via enhancing the Nrf2 expression (Gremmels, de Jong, Hazenbrink, Fledderus, & Verhaar, 2017). Huang et al also demonstrated that SFN and other two structurally related isothiocyanates, benzyl isothiocyanate and phenethyl isocyanate, all prominently decreased damage caused by excessive ROS in human umbilical vein ECs (HUVECs) exposed to oxLDL through increasing Nrf2‐dependent HO‐1 and GCL expressions and subsequently weakening the nuclear factor‐kappa B (NF‐κB) activity (C. S. Huang et al, 2013).…”

Section: Keap1/nrf2 Signaling In Oxidative Stress and Ec Protectionmentioning

confidence: 99%

“…In addition to the mature ECs, Nrf2 has also been shown to play a protective role in endothelial progenitor cells (EPCs), including ECFCs. In the absence of ROS, ECFC angiogenesis was apparently impaired after Nrf2 deficiency; conversely, Keap1 knockdown preserved the angiogenic capacity of ECFCs even in high ROS conditions (Gremmels et al, 2017). Thus, the Keap1‐Nrf2 pathway is crucial for maintaining the proangiogenic ability of ECFCs under conditions with or without oxidative stress.…”

Section: Keap1/nrf2 Signaling In Oxidative Stress and Ec Protectionmentioning

confidence: 99%

Keap1‐Nrf2 signaling pathway in angiogenesis and vascular diseases

Guo

Zhang

2020

J Tissue Eng Regen Med

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The transcription factor, nuclear factor E2-related factor 2 (Nrf2), is highly sensitive to oxidative burst products, including reactive oxygen species (ROS) and reactive nitrogen species. In the cell nucleus, Nrf2 activates various antioxidant genes by binding to the antioxidant response elements. As an adapter for cullin 3/ring-box 1, kelch-like ECH-associated protein 1 (Keap1) ubiquitinates and degrades Nrf2 under physiological conditions. Conversely, with the aggravation of oxidative stress, Keap1-Nrf2 interaction could be much more easily dissociated. ROS play a key role in regulating the redox signaling pathway and affect the vasculature in a dosedependent manner. Long-term production or high concentration of ROS are harmful to the vascular system, while moderate ROS can promote angiogenesis and tissue regeneration. Furthermore, appropriate regulation of oxidative stress mediated via the Keap1-Nrf2 pathway would be beneficial in various diseases associated with abnormal angiogenesis, including diabetes and cancers. Nrf2 deficiency has also been shown to result in significantly impaired survival, proliferation, and angiogenic capacity of endothelial cells in a hind limb ischemia model. Thus, this review will briefly summarize the underlying molecular mechanisms of Keap1-Nrf2 pathway in regulating oxidative stress and also help elucidate the critical role of Keap1-Nrf2 in angiogenesis under physiological and pathological conditions. K E Y W O R D S angiogenesis, diabetes, endothelial cells, Keap1/Nrf2, ROS, tumors

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“…Fourth, ECFCs’ angiogenic activity could be further reduced by the harsh microenvironment of ischemic tissues. For instance, ECFC proliferation and tube formation are affected in the presence of elevated pro-inflammatory signaling [ 129 ], oxidative stress [ 130 ], hypoxia [ 131 , 132 ], and damage-associated molecular patterns (DAMP), such as extracellular histones [ 133 ] and monosodium urate [ 109 ].…”

Section: Manipulation Of Pro-angiogenic Signaling Pathways To Imprmentioning

confidence: 99%

Therapeutic Potential of Endothelial Colony-Forming Cells in Ischemic Disease: Strategies to Improve their Regenerative Efficacy

Faris

Negri

Perna

et al. 2020

IJMS

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Cardiovascular disease (CVD) comprises a range of major clinical cardiac and circulatory diseases, which produce immense health and economic burdens worldwide. Currently, vascular regenerative surgery represents the most employed therapeutic option to treat ischemic disorders, even though not all the patients are amenable to surgical revascularization. Therefore, more efficient therapeutic approaches are urgently required to promote neovascularization. Therapeutic angiogenesis represents an emerging strategy that aims at reconstructing the damaged vascular network by stimulating local angiogenesis and/or promoting de novo blood vessel formation according to a process known as vasculogenesis. In turn, circulating endothelial colony-forming cells (ECFCs) represent truly endothelial precursors, which display high clonogenic potential and have the documented ability to originate de novo blood vessels in vivo. Therefore, ECFCs are regarded as the most promising cellular candidate to promote therapeutic angiogenesis in patients suffering from CVD. The current briefly summarizes the available information about the origin and characterization of ECFCs and then widely illustrates the preclinical studies that assessed their regenerative efficacy in a variety of ischemic disorders, including acute myocardial infarction, peripheral artery disease, ischemic brain disease, and retinopathy. Then, we describe the most common pharmacological, genetic, and epigenetic strategies employed to enhance the vasoreparative potential of autologous ECFCs by manipulating crucial pro-angiogenic signaling pathways, e.g., extracellular-signal regulated kinase/Akt, phosphoinositide 3-kinase, and Ca2+ signaling. We conclude by discussing the possibility of targeting circulating ECFCs to rescue their dysfunctional phenotype and promote neovascularization in the presence of CVD.

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The Transcription Factor Nrf2 Protects Angiogenic Capacity of Endothelial Colony-Forming Cells in High-Oxygen Radical Stress Conditions

Cited by 25 publications

References 54 publications

Nrf2 protects against diabetic dysfunction of endothelial progenitor cells via regulating cell senescence

Nrf2 protects against diabetic dysfunction of endothelial progenitor cells via regulating cell senescence

Keap1‐Nrf2 signaling pathway in angiogenesis and vascular diseases

Therapeutic Potential of Endothelial Colony-Forming Cells in Ischemic Disease: Strategies to Improve their Regenerative Efficacy

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